rs149868979

Positions:

• chr16-23380566-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP5_Moderate BP4

The NM_000336.3(SCNN1B):​c.1688G>A​(p.Arg563Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000861 in 1,614,208 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R563W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000079 (1 hom.)
• Consequence: SCNN1B NM_000336.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.13

Genes affected

SCNN1B (HGNC:10600): (sodium channel epithelial 1 subunit beta) Nonvoltage-gated, amiloride-sensitive, sodium channels control fluid and electrolyte transport across epithelia in many organs. These channels are heteromeric complexes consisting of 3 subunits: alpha, beta, and gamma. This gene encodes the beta subunit, and mutations in this gene have been associated with pseudohypoaldosteronism type 1 (PHA1), and Liddle syndrome. [provided by RefSeq, Apr 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP5: Variant 16-23380566-G-A is Pathogenic according to our data. Variant chr16-23380566-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 561264.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.1114372). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCNN1B	NM_000336.3	c.1688G>A	p.Arg563Gln	missense_variant	13/13	ENST00000343070.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCNN1B	ENST00000343070.7	c.1688G>A	p.Arg563Gln	missense_variant	13/13	1	NM_000336.3	P1

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152250 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000147 AC: 37 AN: 251322 Hom.: 0 AF XY: 0.000162 AC XY: 22 AN XY: 135866

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000787 AC: 115 AN: 1461840 Hom.: 1 Cov.: 32 AF XY: 0.0000825 AC XY: 60 AN XY: 727230

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000514

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000603

Gnomad4 OTH exome AF: 0.000248

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152368 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74514

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000137 Hom.: 0

Bravo AF: 0.000238

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Low renin, low aldosterone hypertension Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneID Lab - Advanced Molecular Diagnostics

Mar 10, 2018

This variant results in an amino acid alteration, replacing an arginine(R) with a glutamine (Q) at position 563, written as p.Arg563Gln or p.Q889H. . in silico prediction algorithms does not provide uniform data regarding the effect of this change on protein structure and function, and it has not been reported in the Clin Var Database (NCBI National Library of Medicine, NIH) but it has been described in 16 alleles out of 121124, in the ExAC database, the majority (9) belonging to heterozygous carries of Latino origin. The variant has been associated with low-renin, low-aldosterone hypertension in South African black and mixed-ancestry individuals, the authors conclude that only a portion of subjects with the R563Q allele fully express the Liddle’s syndrome phenotype (J Hypertens. 2003 May;21(5):921-6). Moreover, there is a positive correlation with pre-eclampsia in this population (BJOG. 2006 May;113(5):595-8). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.84	T;T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.7	L;.;.;.
MutationTaster	Benign	0.74	D;D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.64	N;N;N;N
REVEL	Uncertain	0.46
Sift	Benign	0.32	T;T;T;T
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.090	B;.;.;.
Vest4		0.30
MVP		0.82
MPC		0.19
ClinPred		0.032	T
GERP RS		1.4
Varity_R		0.050
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs149868979; hg19: chr16-23391887;